DESCRIPTION (Adapted from applicants abstract): Nerve growth factor (NGF) and prolactin (PRL) exert actions within numerous tissues in the body, stimulating metabolism as well as growth and differentiation. These factors appear to activate similar intracellular pathways and both factors have been shown to exert trophic actions in lymphocytes.The importance of PRL in immunoregulation has been highlighted in a recent report showing that complete elimination of circulating PRL leads to immunodeficiency and animal death. One of the primary focuses of this proposal is analysis and comparison of the actions of NGF and PRL in lymphocytes.This analysis is now feasible because it has been found that these two factors act in concert in the Nb2 T lymphoma. A number of recent reports implicate two intracellular proteins as integral steps in the signalling pathways activated by both PRL and NGF. One is stathmin, a novel protein that has been proposed to function as an "intracellular relay" that integrates second messenger pathways. The activity of stathmin undoubtedly is regulated by various kinases, because the protein contains multiple phosphorylation sites. The second protein is p11, a protein that associates with the membrane cytoskeleton. This protein has been strongly linked to NGF-induced differentiation and to the actions of PRL in lymphocytes. Phosphorylation and expression of these proteins in response to NGF and PRL, and in response to agents which selectively alter phosphorylation and expression, will be examined in the context of cell differentiation and proliferation. These studies on NGF and PRL should provide new insight into the mechanisms of action of these two important but very poorly understood factors, and will define more clearly the roles of NGF and PRL in regulation of immune function.These studies also will provide new information on the roles of stathmin and p11 as intracellular mediators, and thus provide a framework for further studies of the pathways activated by NGF, PRL and other lymphocyte factors. Information on immune regulation is of particular importance at this time considering the number of diseases which are associated with immunodeficiency. In light of evidence showing that depletion of PRL can lead to a life-threatening immunodeficiency, a study of PRL and its interaction with NGF may be of special significance.